Streptococcus mutans is the major etiologic agent responsible for dental caries, the most prevalent disease in the developed as well as developing countries. Most clinical isolates of S. mutans produce antimicrobial peptides called mutacins. Mutacins are active against a wide spectrum of gram-positive bacteria including pathogens and oral commensals. Thus, mutacin production by S. mutans may play a double role: it provides the producing strain with a competitive edge in gaining dominance in the dental plaque, leading to dental caries. On the other hand, it may protect the human host from gram-positive bacterial infections. The proposed research aims to study the genetic, biochemical and biological aspects of mutacin biogenesis and regulation with the following approaches: Aim 1, to characterize the trans-acting factors for mutacin gene regulation. Aim2, to characterize the cis-acting factors that regulate mutacin gene expression. Aim 3, to determine the structure/function of the mutacin molecule and improve mutacin's properties by genetic engineering. Aim 4, to enhance mutacin biosynthesis and improve fermentation conditions. The proposed research will have a significant impact on two fronts. The first is the alarming surge in resistance to the existing battery of antibiotics by emerging and existing pathogens, and the increasing threat of bioterrorist attack using genetically engineered pathogens resistant to all existing antibiotics. These threats underpin the importance and urgency of finding unconventional antibiotics, to which resistance has not been developed. The second front is understanding the mechanism of gene regulation for mutacin production in S. mutans. This knowledge will help design effective control measures to curb the growth and virulence of S. mutans in the dental _laque.